Association Between ALT Level and the Rate of Cardio/Cerebrovascular Events in HIV-Positive Individuals: The D: A: D Study

Sabin, Caroline A. PhD*; Ryom, Lene MD†,‡; Kovari, Helen MD§; Kirk, Ole MD, DMSci†,‡; de Wit, Stephane MD; Law, Matthew PhD; Reiss, Peter MD#; Dabis, Francois MD**; Pradier, Christian MD††; El-Sadr, Wafaa MD‡‡; Monforte, Antonella d'Arminio MD§§; Kamara, David MSc*; Phillips, Andrew N. PhD*; Lundgren, Jens D. MD†,‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: 1 August 2013 - Volume 63 - Issue 4 - p 456–463
doi: 10.1097/QAI.0b013e318291cd29
Clinical Science

Background: An inverse association between serum alanine aminotransferase (ALT) levels and the risk of myocardial infarction (MI) has been reported in the general population. We investigated associations between ALT levels and the risk of various cardiovascular and cerebrovascular outcomes in a large cohort study of HIV-positive individuals.

Methods: Using Poisson regression, we investigated associations between the latest ALT level and MI, coronary heart disease (CHD), and stroke, after adjusting for known confounders and cumulative/recent exposure to antiretroviral drugs. Analyses were also performed for the end points of all-cause/liver-related mortality and new-onset diabetes mellitus.

Results: By February 2011, participants had experienced 541 MIs, 804 CHD, and 258 stroke events. The MI rate decreased from 3.1/1000 person-years among those with ALT ≤18 U/L to 2.1/1000 person-years among those with ALT >60 U/L. After adjustment for confounders, each 2-fold increment in ALT was associated with a 19% drop in the MI rate {relative rate, 0.81 [95% confidence interval (CI): 0.74 to 0.89], P = 0.0001}. A weaker inverse association was seen for CHD with no indication of a linear association between ALT levels and stroke (P = 0.72). Adjusted relative rates were 0.88 (95% CI: 0.81 to 0.97) and 0.70 (95% CI: 0.54 to 0.92) in those who were hepatitis C virus negative and hepatitis C virus positive, respectively, and 0.72 (95% CI: 0.58 to 0.89) and 0.84 (0.77 to 0.93) in injection drug users and non-injection drug users, respectively. Liver-related mortality and diabetes both demonstrated a positive association with ALT levels, whereas all-cause mortality showed a U-shaped relationship.

Conclusions: Higher ALT levels are associated with lower MI risk in HIV-positive individuals, but with higher risks of liver-related mortality and diabetes mellitus.

*Research Department of Infection and Population Health, UCL, London, United Kingdom;

Copenhagen HIV Programme, University of Copenhagen, Copenhagen, Denmark;

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland;

§Epidemiklinikken M5132, Copenhagen Univ Hosp/Rigshospitalet, Copenhagen, Denmark;

Department of Infectious Diseases, CHU Saint-Pierre Hospital, Brussels, Belgium;

Kirby Institute, University of New South Wales, Sydney, Australia;

#Academic Medical Center, Amsterdam, the Netherlands;

**Université Bordeaux, ISPED, Centre INSERM U897- Epidémiologie-Biostatistique and INSERM, ISPED, Centre INSERM U897-Epidémiologie-Biostatistique, Bordeaux, France

††Département de santé publique, Centre Hospitalier Universitaire, Nice-Sophia-Antipolis University, Nice, France;

‡‡ICAP, Columbia University/Harlem Hospital, New York, NY; and

§§Infectious Diseases Unit, Department of Health Sciences, University of Milan, San Paolo University Hospital, Milan, Italy.

Correspondence to: Caroline A. Sabin, Research Department of Infection and Population Health, UCL, Royal Free Campus, Rowland Hill Street, London NW3 2PF, United Kingdom (e-mail: c.sabin@ucl.ac.uk).

Supported by the Highly Active Antiretroviral Therapy Oversight Committee (HAART-OC), a collaborative committee with representation from academic institutions; the European Agency for the Evaluation of Medicinal Products; the United States Food and Drug Administration; the patient community; and all pharmaceutical companies with licensed anti-HIV drugs in the European Union: Abbott Laboratories, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb, Gilead Sciences, Inc., Viiv Healthcare, Merck & Co, Inc., Pfizer, Inc, F. Hoffman-LaRoche, Ltd., and Janssen Pharmaceuticals. Supported by a grant [grant number CURE/97-46486] from the Health Insurance Fund Council, Amstelveen, the Netherlands, to the AIDS Therapy Evaluation Project Netherlands (ATHENA); by a grant from the Agence Nationale de Recherches sur le SIDA [grant number Action Coordonnée no.7, Cohortes], to the Aquitaine Cohort; The Australian HIV Observational Database (AHOD) is funded as part of the Asia Pacific HIV Observational Database, a program of The Foundation for AIDS Research, amfAR, and is supported in part by a grant from the U.S. National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) [grant number U01-AI069907] and by unconditional grants from Merck Sharp & Dohme, Gilead Sciences, Bristol-Myers Squibb, Boehringer Ingelheim Pharmaceuticals, Inc., Roche, Pfizer, GlaxoSmithKline, and Janssen Pharmaceuticals. The Kirby Institute is funded by The Australian Government Department of Health and Ageing, and is affiliated with the Faculty of Medicine, The University of New South Wales. By grants from the Fondo de Investigación Sanitaria [grant number FIS 99/0887] and Fundación para la Investigación y la Prevención del SIDA en Espanã [grant number FIPSE 3171/00], to the Barcelona Antiretroviral Surveillance Study (BASS); by the National Institute of Allergy and Infectious Diseases, National Institutes of Health [grants number 5U01AI042170-10, 5U01AI046362-03], to the Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA); by grants from the BIOMED 1 [grant number CT94-1637] and BIOMED 2 [grant number CT97-2713] programs and the fifth framework program [grant number QLK2-2000-00773] of the European Commission and grants from Bristol-Myers Squibb, GlaxoSmithKline, Boehringer Ingelheim Pharmaceuticals, Inc., and Roche, to the EuroSIDA study; by unrestricted educational grants of Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Inc., GlaxoSmithKline, Pfizer, Inc., Janssen Pharmaceuticals to the Italian Cohort Naive to Antiretrovirals (The ICONA Foundation); and by a grant from the Swiss National Science Foundation, to the Swiss HIV Cohort Study (SHCS).

M. L. has received unconditional grants from Merck Sharp & Dohme, Gilead; Bristol-Myers Squibb, Boehringer Ingelheim, Roche, Pfizer, GlaxoSmithKline, and Janssen-Cilag. S. d. has received honoraria from Bristol-Myers Squibb and Viiv Healthcare. A. N. P. has received funding for consultancy from Gilead Sciences, Bristol-Myers Squibb, Johnson & Johnson, Viiv Healthcare, and GSK Bio. A. d’A. M. has received funding for Advisory Board membership for Bristol-Myer Squibb, Abbott, Janssen, Gilead Sciences, and Viiv Healthcare. P. R. has served as a scientific advisor to Bristol-Myers Squibb, Gilead Sciences, Grupo Ferrer, GlaxoSmithKline, Janssen, Merck Sharp & Dohme, and ViiV Healthcare. He has served on data safety monitoring boards and endpoint adjudication committees for Janssen and his institution has received honoraria for speaking engagements at scientific conferences from Bristol-Myers Squibb, Gilead Sciences, and GSK. He has received research support from Gilead Sciences, Viiv Healthcare, Merck Sharp & Dohme, Janssen, Bristol-Myers Squibb, Abbott Laboratories, and Boehringer Ingelheim. O. K. has received honoraria, consultancy, lecture fees, and travel grants from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Roche, and Viiv Healthcare. C. P. has received honoraria from Viiv Healthcare, Abbott Pharmaceuticals, and Merck Sharp & Dohme. C. A. S. has received funding for Advisory Board membership, speaker panels, and provision of educational materials for Gilead Sciences, Abbott Pharmaceuticals, Viiv Healthcare, Merck Sharp & Dohme, Janssen-Cilag, and Bristol-Myers Squibb. H. K., F. D., W. E., D. K., L. R., J. D. L. have no conflicts of interest to disclose.

C. A. S. developed the initial study protocol. L. R. prepared study co-ordination, prepared the datasets for analysis and assisted with endpoint review. C. A. S. performed all statistical analysis and prepared the initial draft of the manuscript. All authors have provided management input to the D:A:D Study, contributed datasets, provided input to the development of the manuscript and have seen and approved the final version.

The content of this publication is solely the responsibility of the authors and does not necessarily represent the official views of any of the institutions mentioned above.

The D:A:D participating cohorts and Steering Committee are listed in Appendix 1.

Received December 19, 2012

Accepted February 26, 2013

© 2013 by Lippincott Williams & Wilkins